Medical fluid injector

ABSTRACT

Systems and methods for intelligently delivering fluid to a targeted tissue are described. The systems and methods may include directing a pump to distribute fluid to a targeted tissue and receiving one or more signals from an intracorporeal sensing system, where the one or more signals correspond to one or more sensed feedback parameters at the targeted tissue. The systems and methods may also include determining whether the one or more sensed feedback parameters are within an acceptable range. If the one or more sensed feedback parameters are not within the acceptable range, the systems and methods may include determining an adjusted velocity for the plunger necessary to adjust the pressure of the fluid in the pump so that the one or more sensed feedback parameters move within the acceptable range and directing the pump to distribute the fluid at the adjusted velocity

CROSS REFERENCE TO RELATED APPLICATION

This application is a Continuation of U.S. application Ser. No.13/839,864, filed Mar. 15, 2013, the disclosure of which is incorporatedin its entirety by this reference.

BACKGROUND

Gene therapy, in general terms, includes the use of genetic material asa pharmaceutical agent that can be used to treat disease. Anillustrative form of gene therapy may include using genetic materialthat encodes a functional, therapeutic gene to replace a mutated gene.Other forms may include directly correcting a mutation, or using geneticmaterial that encodes a therapeutic protein drug (rather than a naturalhuman gene) to provide treatment. In gene therapy, the genetic materialthat encodes a therapeutic protein may be packaged within a vector,which is used to get the genetic material inside cells within the body.Once inside, the genetic material may become expressed by the cellmachinery, which may result in the production of a therapeutic protein.

Current methods of providing gene therapy may require isolating tissuewithin the body of a patient with an embolization balloon catheter, andflooding the tissue with a fluid at a high flow rate and a high volumeto cause secretion past capillary walls and into the tissue. This methodmay cause the tissue to swell to a size that is larger than its normalsize. The swelling of the tissue may allow for gene therapy ingredientsto be successfully injected and absorbed into the tissue. However, thismethod does not currently use a device that is capable of successfullyinjecting a sufficient amount of fluid, monitoring the pressure of thetissue to detect pressure changes, and intelligently adjusting the fluiddelivery based upon the pressure changes.

BRIEF SUMMARY

In various embodiments, a system for intelligently delivering fluid to atargeted tissue may include a pump configured to contain a volume offluid at a pressure. In some embodiments, the fluid may include one ormore gene therapy ingredients. The system may also include a processor,an intracorporeal sensing system in operable communication with theprocessor, and a non-transitory, processor-readable storage medium incommunication with the processor. The non-transitory, processor-readablestorage medium may contain one or more programming instructions that,when executed, cause the processor to direct the pump to distribute thefluid to the targeted tissue at an initial velocity, receive one or moresignals from the intracorporeal sensing system, where the one or moresignals correspond to one or more sensed feedback parameters at thetargeted tissue, and determine whether the one or more sensed feedbackparameters are within an acceptable range. The sensed feedbackparameters may be one or more of pressure in a receiving vessel,pressure in the targeted tissue, an image property, a tissue stretchproperty, a tissue conductivity, a tissue ultrasound property, a flowrate in the targeted tissue, a fluid cell count, a fluid particle count,a density of a measurable tracer, and the like. If the one or moresensed feedback parameters are not within the acceptable range, the oneor more programming instructions may, when executed, cause the processorto determine an adjusted velocity for the pump necessary to adjust thepressure of the fluid in the pump so that the one or more sensedfeedback parameters move within the acceptable range and direct the pumpto distribute the fluid at the adjusted velocity. In some embodiments,the storage medium may further include one or more programminginstructions, that, when executed, direct the processor to receive oneor more inputs, wherein the one or more inputs correspond to data thatdefines the acceptable range.

In some embodiments, the system may also include a display in operablecommunication with the processor. The storage medium may further includeone or more programming instructions that, when executed, direct theprocessor to direct the display to display data corresponding to theacceptable range in a user-readable format. The storage medium may alsoinclude one or more programming instructions that, when executed, directthe processor to direct the display to display the one or more sensedfeedback parameters in a user-readable format.

In some embodiments, the system may also include one or more drivingdevices in operable communication with the processing device and anactuation component mechanically connected to the one or more drivingdevices and the pump. The storage medium may include one or moreprogramming instructions that, when executed, cause the processor toactivate the one or more driving devices to cause the actuationcomponent to direct the pump to distribute the fluid to the targetedtissue.

In some embodiments, the pump may be a syringe body, and the system mayalso include a pressure jacket that is configured to surround thesyringe body and prevent the syringe body from expanding. In someembodiments, the system may also include an end plug connected to adistal portion of the syringe. The end plug may be formed of a solidpiece of material and may have a bore therethrough for accuratedistribution of the fluid. The end plug may also be configured toprevent leakage of the fluid from the syringe body. In some embodiments,the intracorporeal sensing systems may include a sensor that is disposedat or near the targeted tissue. In some embodiments, the volume of fluidmay be about 10 ml to about 2000 ml prior to distribution of the fluidto the targeted tissue, and the fluid pressure may about 10 psi to about2000 psi prior to distribution of the fluid to the targeted tissue.

In various embodiments, a method for automatically and intelligentlydelivering a fluid to a targeted tissue may include directing, by aprocessor, a pump to distribute the fluid to the targeted tissue at aninitial velocity, receiving, by the processor, one or more signals froman intracorporeal sensing system, wherein the one or more signalscorrespond to one or more sensed feedback parameters at the targetedtissue, and determining, by the processor, whether the one or moresensed feedback parameters are within an acceptable range. If the one ormore sensed feedback parameters are not within the acceptable range, themethod may also include determining, by the processor, an adjustedvelocity for the pump necessary to adjust the pressure of the fluid sothat the one or more sensed feedback parameters move within theacceptable range and directing, by the processor, the pump to move atthe adjusted velocity. In some embodiments, the method may also includereceiving, by the processor, one or more inputs, where the one or moreinputs correspond to data that defines the acceptable range, directing,by the processor, a display to display data corresponding to theacceptable range in a user-readable format, and directing, by theprocessor, the display to display the one or more sensed feedbackparameters in the user-readable format.

In some embodiments, directing pump to distribute the fluid may includecausing, by the processor, one or more driving devices to activate,wherein activation of the one or more driving devices causes anactuation component to direct the pump to distribute the fluid. In someembodiments, directing the pump to distribute the fluid to the targetedtissue may further include directing the pump to distribute about 10 mlto about 2000 ml of fluid to the targeted tissue at a pressure of about10 psi to about 2000 psi.

In various embodiments, a system for intelligently delivering fluid to atargeted tissue may include a pump configured to contain a volume offluid at a pressure therein, a processor, an intracorporeal sensingsystems in operable communication with the processor, a display inoperable communication with the processor, and a non-transitory,processor-readable storage medium in communication with the processor.The non-transitory, processor-readable storage medium may contain one ormore programming instructions that, when executed, cause the processorto direct the pump to distribute the fluid to the targeted tissue at aninitial velocity and receive one or more signals from the intracorporealsensing systems having a sensor distributed at or near the targetedtissue, receive one or more inputs, determine whether the one or moresensed feedback parameters are within the acceptable range, direct thedisplay to display data corresponding to the acceptable range in auser-readable format, and direct the display to display the one or moresensed feedback parameters in the user-readable format. The one or moresignals may correspond to one or more sensed feedback parameters at thetargeted tissue and the one or more inputs correspond to data thatdefines an acceptable range. If the one or more sensed feedbackparameters are not within the acceptable range, the non-transitory,processor-readable storage medium may contain one or more programminginstructions that, when executed, determine an adjusted velocity for thepump necessary to adjust the pressure of the fluid in the pump so thatthe one or more sensed feedback parameters move within the acceptablerange and direct the pump to distribute the fluid at the adjustedvelocity.

BRIEF DESCRIPTION OF THE DRAWINGS

In the following detailed description, reference is made to theaccompanying drawings, which form a part hereof. In the drawings,similar symbols typically identify similar components unless contextdictates otherwise. The illustrative embodiments described in thedetailed description, drawings, and claims are not meant to be limiting.Other embodiments may be utilized and other changes may be made, withoutdeparting from the spirit or scope of the subject matter presentedherein. It will be readily understood that the aspects of the presentdisclosure, as generally described herein and illustrated in theFigures, can be arranged, substituted, combined, separated, and designedin a wide variety of different configurations, all of which areexplicitly contemplated herein.

FIG. 1 depicts a perspective view of external features of a fluiddelivery system according to an embodiment.

FIG. 2 depicts a perspective view of external components of an injectorhead according to an embodiment.

FIG. 3A depicts a first cross-sectional side view of an injector headand a syringe according to an embodiment.

FIG. 3B depicts a second cross-sectional side view of an injector headand a syringe according to an embodiment.

FIG. 4A depicts the various components of a syringe and a pressurejacket according to an embodiment.

FIG. 4B depicts an alternate view of the various components of thesyringe of FIG. 4A according to an embodiment.

FIGS. 5A and 5B depict a perspective view of various internal componentsof the injector head according to an embodiment.

FIG. 5C depicts a cross sectional view of the injector head across lineC of FIG. 5A according to an embodiment.

FIG. 5D depicts a cross sectional view of the injector head across lineD of FIG. 5A according to an embodiment.

FIG. 6 depicts an intracorporeal sensing unit according to anembodiment.

FIG. 7 depicts a schematic block diagram of various components of acomputing device according to an embodiment.

FIG. 8 depicts a flow diagram of a method of operating a fluid deliverysystem according to an embodiment

FIG. 9 depicts a schematic diagram of a method for detection of a drugextravasation according to an embodiment.

FIG. 10A depicts a graphical illustration of a change in pressure inliver tissue of a dog over a period of time according to an embodiment.

FIG. 10B depicts a graphical illustration of a change in pressure in aphantom liver over a period of time according to an embodiment.

DETAILED DESCRIPTION

The above summary of the present disclosure is not intended to describeeach illustrated embodiment or every possible implementation of thepresent disclosure. The detailed description, which follows,particularly exemplifies these embodiments.

Before the present compositions and methods are described, it is to beunderstood that they are not limited to the particular compositions,methodologies or protocols described, as these may vary. It is also tobe understood that the terminology used in the description is for thepurpose of describing the particular versions or embodiments only, andis not intended to limit their scope which will be limited only by theappended claims.

It must also be noted that as used herein and in the appended claims,the singular forms “a,” “an,” and “the” include plural reference unlessthe context clearly dictates otherwise. Unless defined otherwise, alltechnical and scientific terms used herein have the same meanings ascommonly understood by one of ordinary skill in the art. Although anymethods and materials similar or equivalent to those described hereincan be used in the practice or testing of embodiments disclosed, thepreferred methods, devices, and materials are now described.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where the event occurs and instances where it does not.

For purposes of the description hereinafter, the terms “upper,” “lower,”“right,” “left,” “vertical,” “horizontal,” “top,” “bottom,” “lateral,”“longitudinal,” and derivatives thereof shall relate to the orientationof embodiments disclosed in the drawing figures. However, it is to beunderstood that embodiments may assume alternative variations and stepsequences, except where expressly specified to the contrary. It is alsoto be understood that the specific devices and processes illustrated inthe attached drawings, and described in the following specification, aresimply exemplary embodiments. Hence, specific dimensions and otherphysical characteristics related to the embodiments disclosed herein arenot to be considered as limiting.

The word “proximal” refers to a direction relatively closer to aclinician or operator using the device described herein, and the word“distal” refers to a direction relatively further from the clinician oroperator. For example, the end of a syringe placed nearest the body of apatient is considered a distal end of the syringe, while the end closesto the clinician is a proximal end of the syringe. The terms “axial” or“axially” refer generally to an axis around which the particular objectsbeing referred to are preferably formed (although not necessarilysymmetrically therearound). The term “radial” refers generally to adirection normal to the axis or along a radius of an object having acircular cross-section.

The word “subject” refers to one or more persons and/or animalsreceiving treatment from the apparatus and/or components disclosedherein according to various embodiments. The subject may be any humanpatient, male or female, of any age, race, height, or weight. Inaddition, the subject may be any species of animal, including, but notlimited to, dogs, horses, cows, pigs, rats, mice, and the like.

It is to be understood that the disclosed embodiments may assume variousalternative variations and step sequences, except where expresslyspecified to the contrary. It is also to be understood that the specificdevices and processes illustrated in the attached drawings, anddescribed in the following specification, are simply exemplaryembodiments.

The systems described herein may be used for treatment of any type oftissue, particularly tissue that is amenable to gene therapy treatment.Illustrative examples of tissue that may be used may include, but arenot limited to, liver tissue, muscle tissue, brain tissue, and tumortissue. The liver is an illustrative tissue used as a pathway in genetherapy to deliver a drug as a treatment for various diseases anddisorders through the introduction of an altered gene. To effectivelyadminister the treatment, the liver vasculature is injected with a rapiddelivery that permeates the capillary wall of the liver to allowpenetration of the delivery drug. At some point during the drugdelivery, beyond or including that necessary to achieve the desiredextravasation of the delivery, the capillary and cell walls may becomedamaged. Although damage can be measured post-injection, damagedetection cannot be determined immediately. Measurement of elevatedtransaminases, such as, for example, aspartate aminotransferase (AST)and alanine aminotransferase (ATL) may indicate the extent of damage,but may only be present up to 6 to 8 hours following the procedure. Theelevated ATL and AST levels are indicative of enzymes that are releasedduring repair of the damage. In order to prevent unnecessary or extendedliver damage, a change in the in vivo pressure can be used as an eventto determine the management of the delivery to minimize liver damage.The change that occurs is typically a drop in pressure, but a rapidincrease can be used to determine an occlusion as well. As a simplecontrol, the injection can terminate, continue forward for a timedamount, or operated in a “keep the vein open” (KVO) mode to maintain areduced pressure until saturation is achieved. The use of statistical(i.e., historic) data along with weight, size, and other diagnosticinformation can be used to fine-tune the procedure.

Various embodiments discussed herein are directed generally to a fluiddelivery system that is capable of delivering a large volume of a fluid,such as a fluid containing gene therapy ingredients, to a targetedtissue within a subject. The large volume of fluid may be delivered at ahigh pressure, and the fluid delivery system may be capable ofmonitoring the pressure at the syringe tip and at the targeted tissue.In some embodiments, the fluid delivery system may be able to quicklydiscover and respond to changes in pressure to ensure proper delivery offluid to the targeted tissue.

FIG. 1 depicts external features of a fluid delivery system, generallydesignated 100, according to an embodiment. In various embodiments, thefluid delivery system 100 may generally include an injector body 105, adisplay or a graphical user interface (“GUI”) 115, and a base unit thatmay enclose, among other things, a computing device 120. In certainembodiments, the fluid delivery system 100 may further include one ormore switches, human interface devices, controls, and/or the like, suchas, for example, a foot switch, a hand switch, keyboards, pointingdevices, and/or the like for operating various components of the system.In some embodiments, the fluid delivery system 100 and/or the componentsthereof may be configured to be portable and/or movable. Thus, the fluiddelivery system 100 may include any number of wheels, casters, extensionarms, rotating portions, height adjustable portions, and/or the like.While the current description discloses all of the elements herein asbeing connected as a single unit, those skilled in the art willrecognize that any of the components mentioned herein may be separateand/or remotely connected to the other components without departing fromthe scope of the present disclosure.

In various embodiments, the injector body 105 may be configured asillustrated in FIG. 2. Generally, the injector body 105 may include atleast an injector 107 and a syringe assembly 106. The injector 107 maygenerally be configured to provide a force upon the syringe assembly 106to effectuate distribution of the contents of the syringe assembly, asdiscussed in greater detail herein. In some embodiments, the injector107 may be configured to drive a pump such as, for example, a pistonpump, a reciprocating pump, a rotational pump, a gear pump, aperistaltic pump, a diaphragm pump, or the like.

In some embodiments, the injector 107 may include a housing 108. Thehousing 108 may include one or more enclosure pieces 111, 112 and one ormore access panels 113, which may allow a user to access portions of theinjector 107 covered by the housing or allow for improved access toexposed portions of the injector. In further embodiments, the housing108 may include hinged or slidable access panels 113 for accessingmotors or pumps for moving fluid through the delivery tubing and/oraccessing ports for connecting, for example, a power cord, a controller,a computer, a memory device, a display, a hand switch or footswitch, orvarious combinations thereof. In other embodiments, the housing 108 maybe removably attached to a frame and may be removed to allow access tocomponents such as motors, pumps, syringe holders, tubing managementsystems without the need for an additional access panel 113.

In various embodiments, the syringe assembly 106 may generally include apressure jacket 110, an endplate 125, a securing device 130, and an endplug 135. The end plug 135 may include an opening 140 to allow fluid topass therethrough. In some embodiments, the pressure jacket 110 mayenclose a syringe body therein, as discussed in greater detail herein.In some embodiments, the pressure jacket 110 may be configured to attachthe syringe assembly 106 to the injector 107 through the use of anattachment mechanism, as described in greater detail herein. In someembodiments, the pressure jacket 110 may include one or more openings109, such as slots, windows, or the like, for viewing the fluidcontained in the syringe body. In some embodiments, the pressure jacket110 may include any number of marks and/or the like to assist a user inassembling the pressure jacket to the various other components depictedherein, for determining the amount of fluid within the syringe body,and/or the like.

FIGS. 3A and 3B depict cross-sectional side views of the injector body105 according to an embodiment. In some embodiments, the injector 107may provide a force to drive a plunger 155 in a substantially distaldirection within a syringe body 145 to force fluid out of the syringebody. In some embodiments, the injector 107 may provide a force to drivethe plunger 155 in a substantially proximal direction within a syringebody 145 to stop fluid from exiting the syringe body 145 and/or to drawfluid into the syringe body, as will be described in greater detailherein. In some embodiments, the injector 107 may be configured tocontrol an injection according to a series of flow rate targets over aperiod of time and/or a series of pressure targets over a period oftime.

As also depicted in FIGS. 4A and 4B, the pressure jacket 110 may enclosethe syringe body 145 according to various embodiments. The syringe body145 is not limited by this disclosure, and may generally be any syringebody, pump, or the like now known or later developed. Thus, while theterm “syringe body” is primarily used herein, those skilled in the artmay appreciate that the term may encompass any type of pump,particularly fluid pumps. Illustrative examples of syringe bodies mayinclude, but are not limited to, a bladder syringe, a blow-moldedsyringe, a collapsible syringe, a rigid syringe, a balloon-type syringe,a flexible wall syringe, or the like. In some embodiments, the syringebody 145 may be configured to float or move freely within the pressurejacket 110 without affecting its volume accuracy, but may besufficiently secured to prevent excessive movement within the pressurejacket. In some embodiments, the syringe body 145 may define a fluiddelivery volume therein 150. The fluid delivery volume 150 may beconfigured to house a sufficient volume of fluid to effect delivery to asubject as described herein. In certain embodiments, the fluid volumemay be about 10 ml to about 2000 ml. Specific examples of fluid volumesmay be about 10 ml, about 25 ml, about 50 ml, about 100 ml, about 200ml, about 250 ml, about 500 ml, about 750 ml, about 1000 ml, about 2000ml or any value or range between any two of these values. In someembodiments, the fluid volume may be greater than 2000 ml. In someembodiments, the syringe volume may be different than the fluid volume.In particular embodiments, the syringe volume may be larger than thefluid volume. Thus, in some embodiments, the syringe volume may be about10 ml to about 2000 ml. Specific examples of syringe volumes may beabout 10 ml, about 25 ml, about 50 ml, about 100 ml, about 200 ml, about250 ml, about 500 ml, about 750 ml, about 1000 ml, about 2000 ml, or anyvalue or range between any two of these values. In some embodiments, thesyringe volume may be greater than 2000 ml. In some embodiments, thesyringe body 145 may incorporate a pump system that is attached to alarge volume of fluid to allow an injected to be very small or varylarge and/or adjustable during the procedure.

In various embodiments, the syringe body 145 may be constructed out of amaterial that is capable of withstanding a fluid pressure of about 10psi to about 2000 psi. Specific examples of pressures may include about10 psi, about 25 psi, about 50 psi, about 100 psi, about 250 psi, about500 psi, about 750 psi, about 1000 psi, about 1500 psi, about 2000 psi,or any value or range between any two of these values. In someembodiments, the syringe body 145 by itself may not be capable ofwithstanding the fluid pressure, but when accompanied by the pressurejacket 110 described herein, the syringe body may be able to withstandthe fluid pressure. In some embodiments, the syringe body 145 maygenerally be constructed of materials that do not alter or react withthe contents of the syringe body. In some embodiments, the syringe body145 may be of uniform construction with little or no imperfections onany surface of the syringe body and/or any pump components, particularlyimperfections that may trap air, cells, fluid, or other componentswithin. In particular embodiments, the syringe body 145 may becylindrical in shape where the inside radius of the syringe body isuniform throughout its length, such as, for example, a single hollowtube. In some embodiments, the syringe body 145 may be machined as asingle piece. In other embodiments, the syringe body 145 may be moldedas a single piece. In some embodiments, use of a single hollow tube forthe syringe body 145 may allow for the tube to be extruded or machinedto a tighter tolerance for the radius of the syringe body. Illustrativeexamples of a tight tolerance that are acceptable may include about0.001 inches to about 0.009 inches. Particular examples may includeabout 0.001 inches, about 0.002 inches, about 0.003 inches, about 0.005inches, about 0.007 inches, about 0.009 inches, or any value or rangebetween any two of these values. In some embodiments, the syringe body145 may be constructed of a disposable material. In other embodiments,the syringe body 145 may be constructed of a reusable material so thatthe syringe body can be refilled for subsequent use. In someembodiments, the syringe body 145 may be constructed of polycarbonate,polyethyleneterephthalate (PET), cyclic olefin polymer, polypropylene,polystyrene, polyvinylidene chloride (PVDC), polyethylene napthalate(PEN), high-density polyethylene (HDPE), polypropylene, nylon, glass,glass-containing compounds, glass-like compounds, and/or the like.

In some embodiments, the syringe body 145 may include a distal end 146and a proximal end 147. The distal end 146 of the syringe body 145 maybe configured to receive the end plug 135 to form a seal with the insidesurface of the syringe body by means of a first seal 190. In someembodiments, the first seal 190 may be a separate component from the endplug 135, such as, for example, an added O-ring and/or the like. Inthese embodiments, the first seal 190 may be fixedly attached to the endplug 135 by any means of attachment, including attachment apparatuses,adhesives, and/or the like, or the first seal may be removably attachedto the end plug. In other embodiments, the first seal 190 may befabricated as a portion of the end plug 135. In some embodiments, theend plug 135 may be fabricated as a single solid piece with an opening140 therethrough to ensure that fluid can only travel through theopening, and that no amount of fluid may become trapped in pockets orimperfections within the end plug. The end plug 135 may be constructedof any material that does not interact with the fluid and is capable ofwithstanding fluid pressures as described herein. In some embodiments,the end plug 135 may be constructed of a disposable material. In otherembodiments, the end plug 135 may be constructed of a reusable material.

In some embodiments, the end plug 135 may be secured to the syringe body145 by means of one or more attachment devices 185. The one or moreattachment devices 185 are not limited by this disclosure and maygenerally be any means of providing a secure connection of the end plug135 to the syringe body 145. Specific examples of attachment devices 185may include clips, fasteners, screws, rivets, and/or the like. In someembodiments, the one or more attachment devices 185 may be fabricated asa part of the end plug 135. In some embodiments, the one or moreattachment devices 185 may be fabricated as part of the syringe body145. In yet other embodiments, the one or more attachment devices 185may be standalone attachment devices that are not fabricated as aportion of either the syringe body 145 or the end plug 135. Inembodiments where the attachment devices 185 are fabricated asstandalone devices or as a part of the end plug 135, the distal end 146may include one or more clearance slots 186 that may be configured toreceive the attachment devices and ensure a secure attachment.

In various embodiments, the syringe body 145 may be configured toreceive a plunger 155 therein. In some embodiments, the plunger 155 mayform a seal against the interior of the syringe body 145 by means of oneor more second seals 175. In some embodiments, the second seals 175 maybe a separate component from the plunger 155, such as, for example,added O-rings and/or the like. In these embodiments, the second seals175 may be fixedly attached to the plunger 155 by any means ofattachment, including attachment apparatuses, adhesives, and/or thelike, or the second seals may be removably attached to the firstplunger. In other embodiments, the second seals 175 may be fabricated asa portion of the plunger 155. In various embodiments, the second seals175 may be fabricated of any material commonly known for use inproviding a seal from liquids, particularly pressurized liquids.Specific examples may include rubber, ethylene propylene diene monomerrubber (EPDM rubber), thermoplastic elastomers, polymers, and/or thelike. In various embodiments, the plunger 155 may be fabricated of adisposable material. In other embodiments, the plunger 155 may befabricated of a reusable material. The type of material is not limitedby this disclosure, and may generally be any material now known or laterdeveloped for use in syringe plungers.

In some embodiments, the plunger 155 may be configured to slidably movein a distal and/or a proximal direction within the syringe body 145, asdescribed in greater detail herein. In some embodiments, the plunger 155may be precisely located so that the location of the plunger correspondsto an exact amount of fluid located within the fluid delivery volume150. For example, in some embodiments, movement of the plunger 155 in adistal direction of 0.009 inches may cause 1 ml of fluid to be expelledfrom the fluid delivery volume 150.

In various embodiments, the pressure jacket 110 may be configured toslidably move in relation to the syringe body 145 to encapsulate thesyringe body therein. The pressure jacket 110 may further be configuredto provide a stable means of encapsulating the syringe body 145 toprevent excessive movement of the syringe body, expansion of the syringebody, destruction of the syringe body, and/or the like. By providing astable means of encapsulating the syringe body 145, the pressure jacket110 may act to ensure an accurate pressure, fluid delivery, and volumeof fluid within the syringe body at all times, as described in greaterdetail herein. In some embodiments, the pressure jacket 110 may besecurably positioned around the syringe body 145 by means of theendplate 125 and/or the securing device 130. In particular embodiments,the endplate 125 may contain an opening to allow a distal end of the endplug 135 to extend therethrough. Accordingly, the securing device 130may be secured around the distal end of the end plug 135 to secure theendplate 125 to the pressure jacket 110. For example, the distal end ofthe end plug 135 may contain a plurality of threads so that the securingdevice 130 may act as a nut or the like and can be screwed onto the endplug. In some embodiments, the endplate 125 may be affixed to the endplug 135 and the pressure jacket 110 in such a manner that the pressurejacket is releasably secured to the injector head and also constrainsthe syringe body 145, while still allowing some minimal movement of thesyringe body. Thus, in these embodiments, the pressure jacket 110 may besecurely connected to the endplate 125.

Referring to FIGS. 3A-3B and FIGS. 5A-5D, the injector 107 may includeone or more driving devices 162 according to various embodiments. Thedriving devices 162 may include motors or the like. In some embodiments,the driving devices 162 may be configured to apply a moving force to atleast a portion of the syringe body 145 or components thereof. Thedriving devices 162 may be attached to the housing 108 (FIG. 2) or aframe provided under the housing which maintains the position of thedriving devices during use or the fluid delivery system 100. In someembodiments, the driving devices 162 may have a syringe actuationcomponent 160, such as a piston. The actuation component 160 may includea connector that can be configured to connect to the plunger 155 andallow the motor to advance or retract the plunger in the syringe body145. In certain embodiments, the actuation component 160 may include apiston that contacts the plunger 155 and is capable of advancing theplunger, but not retracting the plunger. In some embodiments, theactuation component 160 may include one or more sensors (not shown)positioned to contact the plunger 155 before or during actuation. Thus,in such embodiments, the driving devices 162 may effectuate discharge ofthe fluid only. In other embodiments, the actuation component 160 mayinclude a piston that contacts the plunger 155 and locks into place viaa removable locking mechanism 165. The removable locking mechanism 165may allow for attachment and detachment of the plunger 155 from theactuation component 160 so that various plungers and/or syringeassemblies may be used with the same injector 107, such as, for example,disposable syringe assemblies. The removable locking mechanism 165 isnot limited by this disclosure, and may include any removable lockingmechanisms now known or later developed, particularly those used forattachment and removal of various syringe components.

In various embodiments, the injector 107 may include a syringe mountingmechanism 172. In some embodiments, the syringe mounting mechanism 172may generally be configured to mount or hold the syringe assembly 106 tothe injector 107. Embodiments are not limited to any particular syringemounting mechanism. For example, in some embodiments, the syringemounting mechanism 172 may be a device configured to accept and hold asyringe or vial holding fluid by removably attaching to the syringe orvial body or flanges associated with the syringe or vial. In otherembodiments, the syringe mounting mechanism 172 may be configured toaccept and hold a secondary device housing a syringe or vial including afluid, such as, for example, the pressure jacket 110 and/or a pressurejacket flange 180. In some embodiments, a securing pin 170 may providean additional or alternative method of securing the syringe assembly 106to the injector 107.

In various embodiments, the syringe mounting mechanism 172 may beassociated with and attached to a framework 173 underlying the housing108 rather than the housing itself. An example of such a framework 173is provided in FIGS. 5A and 5B showing various perspectives of theframework. The framework 173 may generally be constructed of a rigidmaterial that provides mechanical support for the syringe mountingmechanism 172 and/or the actuation component 160. In some embodiments,the framework 173 may substantially improve the accuracy andreproducibility of injections by reducing or eliminating flexion thatcan occur when the syringe mounting mechanism 172 and/or the actuationcomponent 160 are attached to a housing 108 composed of a more flexiblematerial. In some embodiments, the framework 173 may be composed ofsteel, aluminum, another metal or metal alloy, or a high tensilestrength polymer compositions. In some embodiments, the framework 173may be designed to fit within the housing 108 and provide attachmentsites for mechanical components of the injector 107 in addition to thesyringe mounting mechanism 173 and/or actuation component 160.

In various embodiments, the injector 107 may include an injectormounting mechanism 103. In some embodiments, the injector mountingmechanism 103 may generally be configured to mount or hold the injector107 to the fluid delivery system 100. Embodiments are not limited to anyparticular injector mounting mechanism. For example, in someembodiments, the injector mounting mechanism 103 may be a deviceconfigured to accept an arm or the like of the fluid delivery system100, where the injector mounting mechanism contains any means ofsecuring the injector to the arm. In some embodiments, the injectormounting mechanism 103 may be configured to allow the injector 107 torotatably pivot about one or more axes to be positioned in any mannerthat may be desired by a user. In some embodiments, the injectormounting mechanism 103 may be associated with, or attached to, theframework 173. In other embodiments, the injector mounting mechanism 103may be attached to the housing 108.

As depicted in FIG. 6, the fluid delivery system 100 may include one ormore intracorporeal sensing systems, generally designated 200, accordingto various embodiments. The intracorporeal sensing systems 200 maygenerally have a control module 205 and a sensor 210. In someembodiments, the control module 205 may be configured to be anintegrated component of the computing device 120 (FIG. 1). In otherembodiments, the control module 205 may be a standalone component thatis in operative communication with the computing device 120 (FIG. 1),such as by wireless or hardwire communication. In some embodiments, thecontrol module 205 may receive one or more signals from the sensor 210.The control module 205 may optionally interpret the signals as pressurereadings, and may transmit the pressure readings to the computing device120 (FIG. 1).

In various embodiments, the control module 205 may include one or morecontrols 215, one or more communications ports 220, and/or one or moredisplays (not shown). The one or more controls may be used to controlthe sensor 210, such as, for example, turning the sensor on or off,determining what feedback parameters the sensor senses, directing thesensor to the targeted tissue, and/or the like. The one or morecommunications ports 220 may allow the control module 205 to communicatewith the computing device 120 (FIG. 1), as previously described herein.In some embodiments, when the control module 205 is connected to thecomputing device 120 (FIG. 1) via the one or more communications ports220, the computing device may remotely control the control module,thereby deactivating the one or more controls 215.

In various embodiments, the sensor 210 may be delivered to the targetedtissue for sensing the pressure at the targeted tissue before, during,and after delivery of fluid from the syringe assembly 106 (FIG. 2). Thesensor 210 may generally be configured to continuously monitor one ormore feedback parameters at the location of the targeted tissue andquickly transmit signals to the control module 205 indicating the sensedfeedback parameters. Illustrative examples of feedback parameters mayinclude, but are not limited to, pressure in a receiving vessel,pressure in the targeted tissue, temperature, pH, physiological status,an image property, a tissue stretch property, a tissue conductivity, atissue ultrasound property, a flow rate in the targeted tissue, a fluidcell count, a fluid particle count, a density of a measurable tracer,and the like. Accordingly, in some embodiments, the sensor 210 may beconstructed of components that allow for quick transmission of pressuresignals. Specific examples of components that may allow for quicktransmission of signals may include fiber optic components, wirelessradio components, and/or the like. The sensor 210 is not limited by thisdisclosure in the components and/or methods used for sensing. Thus, anysensing devices now known or later developed may be used to sense asdescribed herein. In some embodiments, the sensor 210 may be connectedvia a wired connection to the control module 205, and may be distributedinto the subject via a cannula or the like. In other embodiments, thesensor 210 may be connected via a wireless connection to the controlmodule 205, and thus may be distributed into the subject via injection,oral ingestion, intranasal ingestion, and/or the like. In theseembodiments, the wireless connection may be encrypted or otherwiseprotected by any method now known or later developed to ensure a secureconnection between the sensor 210 and the control module 205.

Referring back to FIG. 2, in various embodiments, the fluid deliverysystem 100 may include delivery tubing for transferring the fluid fromthe syringe assembly 106 to a delivery port and/or the like (not shown)configured to allow injection of the fluid into a subject. In someembodiments, the delivery port may be a port at or near a point of entryon the body of a subject. The delivery tubing may include a tubingextension of any length extending from a syringe connector (such as, forexample, the end plug 135) to the delivery port. In some embodiments,the tubing may include intervening tubing sections that act asextensions or perform specialized functions. The tubing extension maygenerally be of sufficient length to extend from the syringe to thesubject to whom the fluid is to be delivered. Thus, the tubing extensionmay have length of from about 5 in to about 50 in, and in particularembodiments, the tubing extension may have a length of from about 10 into about 50 in, about 15 in to about 45 in, about 20 in to about 40 in,or about 20 in to about 35 in. In certain embodiments, the tubingextension may have a length of 20 in, 36 in, or 48 in. Tubing extensionsof such lengths may be configured to be accepted by a tubing managementsystem while providing sufficient length to allow user maneuverabilityduring the fluid delivery procedure.

The tubing extensions of various embodiments may include one or moreconnectors on each end, and the connector may be any connector known inthe art. For example, a syringe connector may be mounted on an end ofthe tubing extension configured to be attached to the syringe and maybe, for example, a luer or swabable luer type connector. The end of thetubing extension opposite the syringe connector may be configured toattach to a needle or other delivery device and may be a luer orswabable luer type connector. In other embodiments, the end of thetubing extension opposite the syringe connector may be configured as atubing connector such that the tubing connector may attach tointervening tubing sections. In various embodiments, the tubingconnector may be a luer connector. In some embodiments, the tubing mayinclude a communication transmission capability In various embodiments,the communication transmission capability may be wired or wireless, andmay include any number of wires, fiber optic cables, wireless radios, orother means to allow information to be passed from the targeted tissue.

In various embodiments, the fluid delivery system 100 may include anynumber of cords for powering the system using standard AC outlets. Insome embodiments, the fluid delivery system 100 may include an isolationtransformer (not shown). The isolation transformer may generallytransfer electrical power from the AC power source to the variouscomponents of the fluid delivery system 100. In some embodiments, theisolation transformer may isolate the various components from theelectrical power source to prevent system damage from spikes inelectrical activity. In some embodiments, the isolation transformer mayallow for non-medical-grade components to be used in conjunction with,or in place of, the various components described herein.Non-medical-grade components may contain leakage currents that are belowan approved level, but the leakage currents may be limited by theisolation transformer when used as described herein. In someembodiments, the fluid delivery system 100 may include a batteryconfigured to power the system controller in the event that the systemis disconnected from an AC power source. In some embodiments, thebattery may be charged while the fluid delivery system 100 is connectedto an AC power source.

In various embodiments, the fluid delivery system 100 may include asystem monitor device (not shown). The system monitor device may act asan independent monitoring device that functions separately from thecomputing device 120. In some embodiments, the system monitor device maybe physically and/or electrically independent from the computing device120. In some embodiments, the system monitor device may act to shut downand/or disable the fluid delivery system 100 in the event that an unsafecondition is sensed. Unsafe conditions are not limited by thisdisclosure, but may include, for example, unsafe environmentalconditions, unsafe equipment installation, power failure, unsafebiological conditions within the subject, and/or the like.

As provided in FIG. 1, the fluid delivery system 100 of some embodimentsmay include a display 115. Such a display 115 may be a color display ora black and white display. In some embodiments, the display 115 may beconfigured to allow a user to program or otherwise operate the fluiddelivery system 100. In some embodiments, the display 115 may displayreal-time data with regard to the operation of the fluid delivery system100. For example, in certain embodiments, the display 115 may havetouch-screen capabilities or be otherwise configured to allow a user tointeract with the fluid delivery system 100 and, in particular, thecomputing device 120, by manipulating or touching the display. In otherembodiments, the fluid delivery system 100 may include a keyboard,mouse, or other human input device configured to allow the user toprogram or otherwise operate the fluid delivery system. In still otherembodiments, the display 115 may be included as part of a laptop,smartphone, or tablet computer that is electronically associated to thesystem by a hard wired or wireless network. The display 115 may be fixedto the injector body 105, and in other embodiments, the display may bepositioned away from the fluid delivery system 100 and attached to thesystem by a hard wired or wireless network. Such displays 115 may beconfigured to be tilted or swiveled to allow the display to bepositioned by an operator.

In some embodiments, the display 115 may be configured to present orprovide data and information to an operator in an intelligible form orformat, i.e., visually display this information and data in electronicform. In certain embodiments, the fluid delivery system 100 may includea printer 332 (FIG. 7) which may be configured to physically displaythis information and data in print form. The printer 332 (FIG. 7) ofvarious embodiments may be of any type and includes off the shelfink-jet and laser printers. In particular embodiments, the printer 332(FIG. 7) may be configured to print adhesive backed labels. In stillother embodiments, the fluid delivery system 100 may include a speaker334 (FIG. 7) to audibly present this information and data in audibleform. For example, a speaker may be configured to produce an audible“beep” when an injection is complete, or when the fluid has been used upor is nearly used up. In various embodiments, such devices may be incommunication with the computing device 120 or other computing devicethrough output interfaces.

Referring to FIG. 7, in various embodiments, the computing device 120may include one or more components for completing various operations asdescribed herein, for execution of code, and/or for creation andcommunication of data. In some embodiments, the computing device 120 andits various components described herein may be distributed throughoutthe fluid delivery system 100 (FIG. 1) For example, some components mayreside in the display unit 115, the injector head 105, and/or the baseunit. The computing device 120 may include one or more processing units304 (typically referred to as a central processing unit or CPU) thatserve to execute computer-based instructions received in an appropriatedata form and format. Further, the processing units 304 may be in theform of multiple processors executing code in series, in parallel, or inany other manner for appropriate implementation of the computer-basedinstructions. As used herein, the computing device 120 may be operablyconfigured to execute appropriate software to perform and implement theprocessing steps of the methods and systems disclosed herein. Thecomputing device 120 may have a computer-readable storage medium capableof storing computer-readable program code or instructions that cause theprocessing units 304 to execute, configure, or otherwise implement themethods, processes, and transformational data manipulations discussedherein. Still further, the computing device 120 may be in the form of apersonal computer coupled to the fluid delivery system 100, a processorformed integrally with the fluid delivery system, a computer providedremotely from the fluid delivery system, or any other type of computingdevice having the necessary processing hardware to appropriately processdata to effectively implement the processes described herein.Illustrative examples may include, but are not limited to, a smartphone,a personal digital assistant (PDA), a tablet computing device, aphone-tablet hybrid (e.g., a “phablet”), a laptop computer, a netbook,an ultrabook, a desktop computing system, and/or the like.

The computing device 120 may further include a system bus 306 tofacilitate appropriate data communication and processing informationbetween the various components of the computing device. The system bus306 may be any of several types of bus structures, including a memorybus or memory controller, a peripheral bus, or a local bus using any ofa variety of bus architectures. In particular embodiments, the systembus 306 may facilitate data and information communication between thevarious components (whether internal or external to the computing device120) through one or more interfaces.

In various embodiments, the computing device 120 may include systemmemory 308 with computer storage media such as volatile and non-volatilememory, ROM, and/or RAM. A basic input/output system (BIOS) withappropriate computer-based routines may assist in transferringinformation between components within the computing device 120 and canbe stored in ROM. The RAM portion of the system memory 308 may typicallycontain data and program modules that are immediately accessible to orpresently being operated on by the processing units 304 such as, forexample, an operating system, one or more application programminginterfaces, application programs, program modules, program data, andother instruction-based computer-readable code.

The computing device 120 may also include other removable ornon-removable, volatile or non-volatile computer storage media products.For example, the computing device 120 may include a non-removable memory310 that communicates with and controls a hard disk drive 312, such as,for example, a non-removable, non-volatile magnetic medium. Thecomputing device 120 may further include a removable, non-volatilememory interface 314 that communicates with and controls a magnetic diskdrive unit 316 (which may read from and write to a removable,non-volatile magnetic disk 318), an optical disk drive unit 320 (whichmay read from and write to a removable, non-volatile optical disk, suchas a CD ROM 322, a DVD disc, a Blu-Ray disc, and/or the like), aUniversal Serial Bus (USB) port for use in connection with, for example,a removable memory card 323 and/or the like. Other removable ornon-removable, volatile or non-volatile computer storage media may beused, including, but not limited to, magnetic tape cassettes, DVDs,digital video tape, solid state RAM, solid state ROM, and the like.These removable or non-removable, volatile or non-volatile magneticmedia may be in communication with the processing unit 304 and othercomponents of the computing device 120 via the system bus 306. Thedrives and their associated computer storage media may provide storageof operating systems, computer-readable instructions, applicationprograms, data structures, program modules, program data, and otherinstruction-based computer-readable code for the computing device 120(whether duplicative or not of the information and data in the systemmemory 308).

In some embodiments, the computing device 120 may include one or morediscrete computer-readable media components or other media that can beaccessed by the computing device, such as, for example, volatile media,non-volatile media, removable media, non-removable media, and the like.In certain embodiments, the computer-readable media may be stored in anon-transitory storage medium including, but not limited to, randomaccess memory (RAM), read only memory (ROM), electrically erasableprogrammable read only memory (EEPROM), flash memory, or other memorytechnology, CD-ROM, digital versatile disks (DVDs), Blu-Ray discs, otheroptical disk storage, magnetic cassettes, magnetic tape, magnetic diskstorage, other magnetic storage devices, or any other medium which maybe used to store the desired information and which can be accessed bythe computing device 120. In some embodiments, the computer-readablemedia may include communications media, such as computer-readableinstructions, data structures, program modules, or other data in amodulated data signal such as a carrier wave or other transportmechanism. In other embodiments, the computer-readable media may includeany information delivery media, wired media (such as a wired network anda direct-wired connection), and wireless media (such as acousticsignals, radio frequency signals, optical signals, infrared signals,biometric signals, bar code signals, etc.). Combinations of any of theabove are also included within the scope of computer-readable media.

In various embodiments, the fluid delivery system 100 may be configuredto allow a user to enter commands, information, and data into thecomputing device 120 using the touch-screen of the GUI display 115 viaan operator input interface 328. In other embodiments, an operator mayenter commands, information, and data into the computing device 120using other attachable or operable input devices, such as a keyboard324, a mouse 326, a remote control device, a microphone, a trackball, ajoystick, a touchpad, a scanner, a tablet computer, and/or the like, viathe operator input interface 328. Any arrangement that facilitates theinput of data and information to the computing device 120 from anoutside source may be used including, for example, a hard wiredconnection or an access via a wireless network device, such asBluetooth, a wireless internet connection, a cellular connection, and/orthe like. As discussed, these and other input devices are oftenconnected to the processing unit 304 through the operator inputinterface 328 coupled to the system bus 306, but may be connected byother interface and bus structures, such as, for example, a parallelport, a game port, a USB port, and/or the like.

In some embodiments, the computing device 120 may operate in a networkenvironment 338 through the use of a communications device 340, whichmay be either integrated with the computing device, or may be remotelyaccessed by the computing device. This communications device 340 may beoperable by and in communication with the other components of thecomputing device 120 through a communications interface 342. Using suchan arrangement, the computing device 120 may connect with or otherwisecommunicate with one or more remote computers, such as a remote computer344 of an external information system, which may include some or all ofthe components described above in connection with the computing device120. Using appropriate communications devices 340 such as, for example,a modem, a network interface, an adapter, a telephone line, a cableline, a fiber optic line, a T3 line, a cellular telephone connection, aWi-Fi network, and/or the like, the computing device 120 may operatewithin and communicate through a local area network (LAN) and a widearea network (WAN), such as the network 338 shown in FIG. 7, but mayalso include other networks such as a virtual private network (VPN), anoffice network, an enterprise network, an intranet, the Internet, and/orthe like. It may be appreciated that the network connections shown areexemplary and other means of establishing a communications link betweenthe computers 120, 344 may be used.

Generally, the embodiments described herein may be configured tointelligently deliver a fluid that is sufficient for delivery to anaverage subject based upon models and calculations that may beprogrammed into the computing device 120, as described herein. In someembodiments, a user may input various parameters into the computingdevice 120 when the fluid is loaded into the fluid delivery system 100.Illustrative examples of the various parameters may include, but are notlimited to, information about the subject to which the fluid isdelivered, (i.e., height, weight, medical conditions, and the like),identification of the tissue and/or area to receive treatment, type oftreatment to be delivered to the subject, measurements of the tissueand/or area to receive treatment, and/or the like. In some embodiments,the fluid delivery system 100 may be configured to determine the volumeof fluid to be delivered, as well as an amount and/or concentration ofgene therapy ingredients to be delivered, which may be based on theparameters received from the user. In some embodiments, the fluiddelivery system 100 may be further configured to deliver a dose of fluidand/or gene therapy ingredients having a desired activity level based onthe parameters received from the user. In some embodiments, the fluiddelivery system 100 may be configured to deliver the fluid and/or genetherapy ingredients at a specified pressure, and may modify the pressureof delivery based upon feedback received from the intracorporeal sensingsystems 200 (FIG. 6), as described herein.

In various embodiments, the computing device 120 may be configured todirect the injector body 105 (FIG. 1) to administer the fluid to asubject, monitor the pressure and rate of administration of the fluiddelivery at the injector body, and receive feedback from theintracorporeal sensing systems 200 (FIG. 6). Based upon the feedbackreceived, the computing device 100 may calculate any necessary changesto the pressure and rate of delivery and direct the injector body toadjust the pressure and rate of delivery accordingly. In particularembodiments, the computing device 120 may monitor the pressure and rateof administration of the fluid delivery at the end plug 135 (FIG. 2).Such embodiments may require one or more pressure sensors positioned atthe end plug 135 (FIG. 2) and/or at other portions of the injector body105 (FIG.1) that are in communication with the computing device 120,such as through the communications interface 342 or the input interface328. In other embodiments, the force on the plunger may be used tomeasure the pressure in the syringe. In yet other embodiments, thetorque and/or the amperage of the one or more driving devices 162 (FIG.3A) may be used to determine the pressure in the syringe.

In some embodiments, the computing device 120 may calculate anynecessary changes to the pressure and rate of delivery using one or morealgorithms that have been programmed based upon mathematical and/orphysical models of the target tissue for an average subject. One suchphysical model that has been developed for determining pressure and flowof fluid is a dynamic anthropomorphic cardiovascular phantom disclosedin U.S. Patent Application Publication No. 2009/0226867 to Kalafut etal., the entire contents of which are incorporated herein by reference.Another physical model may be a liver model that may be used to mimicthe pressure and flow response of fluid within a liver, particularlywith regards to an injection of fluid into the liver model. By injectingfluid into the liver model and then observing the results of theinjection, a researcher can devise an algorithm for the computing device120 that corresponds to expected pressure and flow response in an actualliver when fluid is injected into a subject as described herein. Whilethe above models refer to cardiac and hepatic tissue, those skilled inthe art will recognize that any tissue may be used.

The fluid delivery system 100 may further be configured for priming(i.e., purging air from the tubing system) and delivering a fluid to asubject, as previously described herein. In addition, the fluid deliverysystem 100 may facilitate safe delivery of the fluid to multipledestinations, such as, for example, dose delivery to multiple tissueareas and/or multiple subjects.

The fluid delivery system 100 may be further configured to providefeedback information to a user. For example, in some embodiments, thefluid delivery system 100 may provide the user with informationregarding the administration such as, but not limited to, the dosage offluid delivered to the subject by mass (mg), volume (ml), dosing time(i.e., the time required for delivery), delivery time (i.e., the time ofday), date, and/or fluid pressure in the delivery system duringdelivery. In some embodiments, the fluid delivery system 100 mayreference subject data to determine the amount of fluid administered tothe particular subject over time and provide a warning to the operatorif the amount of fluid and/or the pressure of the fluid is too high ortoo low. In various embodiments, the information may be provided to theuser in real time.

Following administration or the completion of an administrationprotocol, the fluid delivery system 100 may provide a summary of theprocedure including any relevant data. For example, in variousembodiments, the system may provide the dosage of fluid delivered to thesubject by mass (mg), volume (ml), the amount of another pharmaceuticalcomposition delivered to the subject (mg/ml), dosing time (i.e., thetime required for delivery), delivery time (i.e., the time of day),date, and fluid pressure in the delivery system during delivery, and/orthe like. Data may be provided either in real time during performance ofthe protocol and/or in summary form after completing. The data may beprovided numerically and/or graphically. In certain embodiments, thedisplay 115 may provide both numeric and graphic data simultaneously.

The fluid delivery system 100 may further provide subject identificationand any critical data such as, weight, age, disease being treated ortested for, the procedure to be performed, the location of theinjection/infusion site, and the like and various combinations thereof.Such data may be received at the time of or prior to the procedure. Incertain embodiments, the operator may input a subject identification,and the fluid delivery system 100 may retrieve appropriate subject datafrom electronically archived records using a computer network orInternet connection. In still further embodiments, the fluid deliverysystem 100 may store subject information for more than one procedure.

Referring to FIGS. 1-7, in operation, the syringe body 145 may be loadedwith any amount of a composition and the syringe body 145 may beinstalled into the injector 105. The plunger 155 may be specificallypositioned so that the composition within the syringe body is aparticular volume and pressure. The syringe actuation component 160 maybe advanced to push the plunger 155 in a distal direction. The syringeactuation component 160 may be controlled by the computing device 120 toincrease in speed, decrease in speed, stop, or reverse the plunger inthe proximal direction depending on a desired pressure and or flow ofthe contents of the syringe body 145. Adjustments to the movement of thesyringe actuation component 160 may be of any size (i.e., a large changein speed or a small change in speed) to ensure an exact volume andpressure is achieved. In some embodiments, the syringe actuationcomponent 160 may first move the plunger 155 in a distal direction todisplace blood in or around the tissue, and then increase the speed ofthe plunger movement to inject the fluid into the tissue.

User control of the fluid delivery system 100 may be carried out by anysuitable means. For example, in some embodiments, a user may triggerdelivery of the fluid using the GUI interface by pressing a button onthe screen. In other embodiments, an external button may be used totrigger delivery. The external button may be configured to be activated,for example, by hand or using a foot pedal. In other embodiments, thedelivery of the fluid may be coordinated with a physiological parameter,such as, for example, a heart phase, a vessel pressure, or a breathphase. In yet other embodiments, delivery may be triggered by thecomputing device 120. In further embodiments, the delivery may betriggered by a remote hand controller. In some embodiments, the fluiddelivery system 100 may include an interrupt button that is configuredto allow an operator to pause or abort an injection procedure in theevent of, for example, subject discomfort or an emergency, whilebypassing the GUI display 115, which also can be configured to allow theuser to pause or abort an injection procedure. An interrupt button maybe connected to LEDs and/or a printed circuit board to provide visualand/or auditory alarms when the interrupt button has been activated.

Various embodiments are directed to methods for using the fluid deliverysystem 100 and devices encompassed by the fluid delivery system. In someembodiments, before starting the injection procedure, the operatorand/or the computing device 120 may determine the desired amount offluid to be delivered to the subject based on the tissue to be treated,biological characteristics of the subject, and/or the like. The methodsof various embodiments may include the step of inputting suchinformation before beginning the procedure.

In certain embodiments, methods may further include generating a list ofprocedures to be performed over a time period. While the informationprovided in such a list may vary, in some embodiments, the list mayinclude subject ID numbers, type of procedure, amount of fluid to bedelivered to the identified subject, the time necessary of the procedureand/or a projected start time for the procedure, and the like. Inparticular embodiments, the information required for such a list may bereceived by the fluid delivery system 100 before initiation, and inother embodiments, information for the list may be provided before theinitiation of the procedure for each individual subject. In still otherembodiments, information for the list may be received from a remotelocation, and subject information may be provided to the system via anInternet or other network connection.

Initialization may include any number of steps necessary to prepare thesystem for delivery of a fluid. In some embodiments, initialization mayinclude filling the system including all tubing and connectors withsaline or another medical fluid to remove air from the fluid path, suchas, for example, flushing the system. In some embodiments, the step offlushing the system may be carried out by manually filling variouscomponents with saline before connecting to the syringe. In otherembodiments, the various components and/or various portions thereof maybe prefilled with saline or another medical fluid before packaging.

In various embodiments, the method presented above may further includethe step of delivering the fluid to the subject. Delivering the fluidmay include the steps of inserting a needle or other delivery deviceinto the subject at an appropriate location such as a vein, an artery,or the targeted tissue. For mice, the tail vein is commonly used. Theuser may secure the needle to the subject using, for example, medicaltape, and the needle and needle tube may be primed to introduce bloodinto the needle and needle tube. A primed extension tube or primeddiffusion chamber may be connected to the needle and needle tube toprovide a wet-wet connection. The fluid may be delivered to the subjectby activating the one or more driving devices 162 causing the plunger155 to be advanced, thereby delivering the appropriate volume of fluidto the subject.

In some embodiments, another injection of the fluid may be delivered tothe subject. In such embodiments, the procedure may continue byrepeating the operations provided above. Notably, the initializationoperations may be omitted during repeated delivery of fluid. In someembodiments, the fluid delivery system 100 may determine that thepressure and/or flow response in the targeted tissue should be adjustedand may adjust the pressure and rate of transmission accordingly. In theevent that no further injections are necessary, the procedure may beterminated using a shutdown protocol, which may include flushing thesystem with medical fluid.

FIG. 8 depicts a flow diagram of a method of operating the fluiddelivery system 100 (FIG. 1) according to an embodiment. In someembodiments, a processor may be connected to a non-transitory,processor-readable storage medium that contains one or more programminginstructions that, when executed, cause the processor to complete themethod described herein.

In various embodiments, the processor may direct 405 the plunger to movein the syringe body. In particular embodiments, the plunger may move ina distal direction to cause distribution of fluid to targeted tissue, asdescribed in greater detail herein. The processor may direct the plungerto move at a particular velocity to ensure proper movement to thetargeted tissue and/or a desired pressure is maintained in the fluid. Aspreviously described herein, the plunger and the syringe body may be inthe form of a pump, where the processor directs 405 the pump todistribute the fluid to the targeted tissue. In some embodiments, theprocessor may direct 405 the plunger by activating one or more drivingdevices that cause the actuation component to apply a force to the pumpor plunger.

As the fluid is directed to the targeted tissue, the processor mayreceive 410 one or more signals from an intracorporeal sensing systemsthat has one or more sensor at or near the targeted tissue thatcorrespond to one or more sensed feedback parameters sensed by thesensors of the intracorporeal sensing system. In some embodiments, thesensors may be located at or near the targeted tissue, and may beconfigured to sense the targeted tissue in real time. The processor mayreceive 410 the signals immediately prior to the sensing, as describedherein. In addition to receiving 410 one or more signals, the processormay receive 415 one or more inputs. The inputs may be received from auser, program code, and/or the like, and may generally containinformation regarding acceptable ranges for the sensed tissue, which isbased upon the type of tissue being sensed and certain characteristicsof the subject, as described herein.

The computing device may determine 420 whether the one or more sensedfeedback parameters are within the acceptable ranges, and may optionallydisplay 425 the sensed feedback and the acceptable range on a display.If the sensed feedback parameters are determined 430 to be within theacceptable range, the process may determine 445 whether any additionalfeedback is sensed by the sensors. If additional feedback is sensed, theprocesses may repeat. If no additional feedback is sensed, the processesmay end.

If the computing device determines 430 that the feedback parameters arenot within the acceptable range, it may determine 435 an adjustedvelocity necessary to bring the feedback parameters within theacceptable range. The computing device may determine 435 the adjustedvelocity via any number of inputs, via a preprogrammed algorithm, and/orthe like, as previously described herein. The computing device mayadjust 440 the plunger velocity by sending a signal to the plungerand/or the one or more driving devices to adjust the velocityaccordingly. As the velocity is changed, the computing device mayactively receive additional signals and the processes described hereinmay repeat until the feedback parameters are within the acceptablerange. The processes described herein may be continuous and active, withthe processor continuously receiving signals and adjusting velocityuntil the fluid delivery process is complete.

EXAMPLES Example 1 Injector Control

The injector described in this Example is designed to allow moresophisticated and flexible types of control over injection proceduresthan is available with current injectors. As a result, the injector mayaid in the discovery of new medical procedures and enable the consistentperformance/delivery of an optimal procedure to each patient.

Injection control systems can be arrayed in a hierarchy from simplest tomost complex. The following level designations are for reference only.Simplest is a gravity infusion with no control system, where the fluidis allowed to freely run into the patient. Second is a manual infusion,such as by using, for example, a handheld or hand-operated syringe. Somecontrol is possible, but it is not consistent and cannot be long term. Anext level is a fixed pressure with a restriction, such as, for example,a gravity-driven flow with a restriction. The fixed pressure with arestriction is often user-adjustable, and the flow rate is estimated bycontrolling a drop rate. Next is an electromechanical system, preferablywith a computer-controlled user interface and operation. A simplestepper motor driven syringe pump is one example. There is no feedbackloop, and there can be some safety checks. More sophisticated systemsare able to deliver higher levels of control using feedback loops withinthe system to servo control the delivery to allow adjustment to externalvariations in aspects such as fluid path restrictions or back pressurebuild-up. Most current power injectors are capable of this type ofoperation.

Providing a measurement in the physiological system allows feedback tocontrol a physiologically relevant parameter that can help ensure thatdelivery is sufficient for the desired goal but is not excessive so asto cause damage or other phenomena. Potential feedback parametersinclude, for example, pressure in the receiving vessel, pressure intissue, temperature in a vessel, temperature in tissue, flow in avessel, a property of an image such as density of a voxel, tissuestretch, tissue conductivity, tissue ultrasound properties, flow rate inthe targeted tissue, a fluid cell count, a fluid particle count, thedensity of a measurable tracer, and the like. As is known in the medicalarts, the property being measured by an imager depends upon the type ofthe imager, such as, for example, X-ray attenuation in CT imaging andproton density, T1, or T2 in MR imaging.

A second dimension or aspect to control is the one or more variablesthat are being controlled. Normal injections control flow rate until atotal volume is delivered or a specified time period is met. A moresophisticated control also allows setting the acceleration or ramp bythe user or the system (for example, to reduce catheter whip inangiography). If the injector can deliver multiple fluids in oneinjection, the composition or ratio is a variable that can be controlledto provide a better result for the patient. It is possible to controlpressure as the primary parameter. An angioplasty balloon controllerwould have this function, where the fluid is delivered to inflate theballoon, but the amount or volume of fluid is not the primary parameterof importance. The parameters would be pressure and time, preferablywith controlled ramp up and ramp down in pressure. The parameter beingcontrolled or optimized can be received from a sensor or from an imager.In the current system, pressure feedback from the liver vein fits thiscategory.

Controlling one parameter with a limit to or on a second parameterprovides yet another level of control. Some current injectors controlflow rate with a maximum pressure limit that can be set by the user. Inan angioplasty, controlling pressure with a maximum volume to bedelivered would result in an acceptable algorithm to resolve a leakingballoon issue. For example, in CT injections, delivering a flow rate of10 ml/second with a pressure limit of 100 psi means that the fluiddelivery system will deliver the fluid at 10 ml/second independent ofthe pressure needed, until it requires 100 psi or more. Then the fluiddelivery system either limits the pressure at 100 psi and delivers lessflow until the full volume selected is delivered, or may optionally haltthe delivery because the pressure limit has been reached. The controllerof this system provides further capability around limiting behavior inthat the user may select more than one parameter to be used as a limit,such as, for example, programming an injection to achieve a certainintravascular pressure for a certain duration can have limits to bothflow rate and volume delivered in that phase or overall. Another exampleis delivering a flow rate for a total volume with a limit on pressure inthe vessel, pressure in the system or syringe, and time/duration.Limits, at the discretion of the user, are applied to each phase of theinjection or procedure or to cumulative parameters such as time orvolume for multiple phases. The control system of an embodiment providesa number of options to the user in regards to the actions that are takenwhen a limit is reached. As mentioned above, the simplest is to halt theinjection when the a limit is reached. A second is to only alert theuser that a limit has been reached and not change behavior in any way,unless a capability of the system has been reached. A third is to holdthe limit parameters at their limits and reduce or extend otherparameters to allow the procedure to continue to completion or untilanother limit is reached, with or without alerting the user real time. Afourth option is to alert the user and require some action within acertain timeframe, such as, for example, stopping unless the userpresses a continue button. The type of interaction may depend upon thetype of user control. The real time information or feedback to theoperator includes alerting the user when limits are being approached sothat limiting behavior is averted.

The next level of control allows different parameters to be controlledduring different phases or times during the injection or procedure withother parameters being in the limit role. When flow rate or pressure isthe controlled parameter that the system seeks to maintain within theoperator defined range, one or more controlled parameters in each phaseare used. The system used one or more action parameters to adjust andkeep the controlled parameters within the range. For example, the pumpwould increase flow rate if the intravascular pressure is lower than thetarget range. Increased flow rate is achieved by increasing the motorcurrent and/or the voltage to the pump, which are commonly parametersnot visible to the user. Thus, flow rate, motor voltage, and motorcurrent are action parameters. Furthermore, one or more durationparameters are used to determine the duration or completion of the phaseor injection. In addition, one or more limiting parameters are set tohelp assure safe or proper operation of the system. There are also oneor more monitor or measured parameters which the system assesses ormeasures and reports to the user, use in the control algorithm orprocess (for example, to anticipate conditions) or use in some otherway. The user may not be aware of the system's action or measuredparameters. Thus, with the injector described herein, a volume of genetherapy fluid (the duration parameter) is first delivered at a low ormoderate flow rate (the controlled parameter) with a relatively lowin-vein pressure limit (a limiting parameter) to ensure that the livervessels are filled with the gene therapy fluid and not blood orcontrast, and optionally with a set syringe pressure limit (a secondlimiting parameter) to ensure safe operation. The second phase of theprocedure ramps up the flow rate quickly (the controlled parameter) tobuild up pressure in the vein (a duration parameter) and drive the fluidinto the tissue with a venous pressure limit (a limiting parameter) toprevent damage. The transition to the third phase occurs when a certainvenous pressure is achieved (duration parameter for the second phase).The venous pressure (controlled parameter) is held for a time (durationparameter) to maintain the “stretch” and enable the fluid to diffuseinto the extravascular space, with a flow rate limit (limit parameter)in case there is too much leakage, and optionally with a flow ratelimit(limit parameter) as well. The final phase is a venous pressureramp (controlled parameter) down over a time (duration parameter) toconsistently and controllably return the system to normal pressure. Inthis situation, the ability to select and vary the parameter that isbeing controlled, the duration parameter(s), and the parameter(s) thatare serving as the limit(s) improves the ability to optimize andcustomize the injection. The transition between the second and thirdphase was based on achieving a pressure, and not a total volumedelivered, time, or a flow rate achieved. This is another example ofmixed controls, where the end of one phase and the beginning of anotheris determined by the value of an alternate control parameter.

To achieve the next level of adjustment or control algorithmsophistication, duration parameters or limit parameters that aredependent upon or recognize the patient's physiological condition orresponse to the procedure are employed. FIG. 9 discloses such asituation. In the second phase described above where the flow rate andpressure in the vein rapidly increases, a sudden drop in pressure mayresult where the liver “cracks” or the gateway to an alternative fluidpath opens, such as to the arterial flow. In this case, the system canautomatically enter a next phase that maintains that pressure for afixed time. Alternatively, in that next phase, the pressure could beslowly decreased or increased, as shown in FIG. 9. The particular actionto be performed will be a function of the specific physiology andprocedure for which the system is being used.

Example 2 Liver Phantom Test Injection Using a Dog Liver PressureProfile

A Medrad Mark V ProVis® Injection System (Bayer HealthCare, IndianolaPa.) was used to inject fluid into a liver phantom model. The liverphantom model was constructed to mimic a typical dog liver under variousbiological conditions. The device, constructed as a controlled andprogrammable pressurized chamber is used to simulate the pressure andflow characteristics of the targeted organ or region of interest. Aninjection protocol is programmed into the injection system, then thefluid media is injected into the phantom. As the programmed injection isdelivered to the phantom, the results are captured by the installedphantom sensors, such as, but not limited to, pressure sensors, fluidflow sensors, and temperature sensors. The data is then saved in memoryand charted for the user to read, evaluate and manipulate. The user canthen use the recorded results to modify or improve the programmedinjection as necessary or desirable.

Pressure of the fluid in the phantom model was introduced using aMentor™ Pressure Simulator (Merit Medical, South Jordan Utah), and thepressure of the phantom model was sensed using a PCU-2000 PressureControl Unit (Millar Instruments Inc., Houston Tex.). Fluid was injectedinto the phantom liver at a rate of 0-40 ml/second for 6 seconds todeliver 120 ml of fluid, and then was injected at a rate of 40 ml/secondfor 2 second to deliver 80 ml of fluid through an 8 French catheter. Asimilar process was carried out in a live animal model. A standardimage-guided insertion procedure employed in the clinic was used forplacing a balloon catheter into the right lateral hepatic vein or renalvein to target the liver or kidney, respectively. The total injectionvolume was 800 ml delivered in 20 seconds (40 ml/s) for the liver, and55 ml in 11.7 seconds (4.7 ml/s) for the kidney.

Results of the test are displayed in FIGS. 10A and 10B. The results showthat the waveforms are generally the same and can be tuned to beidentical by changing parameters of the liver phantom.

Although various embodiments have been described in detail for thepurpose of illustration, it is to be understood that such detail issolely for that purpose and that the disclosure is not limited to thedisclosed embodiments, but, on the contrary, is intended to covermodifications and equivalent arrangements. For example, it is to beunderstood that this disclosure contemplates that, to the extentpossible, one or more features of any embodiment can be combined withone or more features of any other embodiment.

1. A system for intelligently delivering fluid to a targeted tissue, thesystem comprising: a pump configured to contain a volume of fluid at apressure; a processor; an intracorporeal sensing system in operablecommunication with the processor; and a non-transitory,processor-readable storage medium in communication with the processor,wherein the non-transitory, processor-readable storage medium containsone or more programming instructions that, when executed, cause theprocessor to: direct the pump to distribute the fluid to the targetedtissue at an initial velocity; receive one or more signals from theintracorporeal sensing system, wherein the one or more signalscorrespond to one or more sensed feedback parameters at the targetedtissue, wherein the one or more sensed feedback parameters comprise oneor more of pressure in a receiving vessel, pressure in the targetedtissue, an image property, a tissue stretch property, a tissueconductivity, a tissue ultrasound property, a flow rate in the targetedtissue, a fluid cell count, a fluid particle count, and a density of ameasurable tracer: determine whether the one or more sensed feedbackparameters are within an acceptable range; if the one or more sensedfeedback parameters are not within the acceptable range, determine anadjusted velocity; and direct the pump to distribute the fluid at theadjusted velocity.
 2. The system of claim 1, further comprising one ormore programming instructions, that, when executed, direct the processorto: receive one or more inputs, wherein the one or more inputscorrespond to data that defines the acceptable range.
 3. The system ofclaim 1, further comprising: a display in operable communication withthe processor; and one or more programming instructions that, whenexecuted, direct the processor to: direct the display to display one ormore of data corresponding to the acceptable range in a user-readableformat and the one or more sensed feedback parameters in a user-readableformat.
 4. The system of claim 1, further comprising: one or moredriving devices in operable communication with the processing device;and an actuation component mechanically connected to the one or moredriving devices and the pump, wherein the one or more programminginstructions that, when executed, cause the processor to direct the pumpto distribute the fluid to the targeted tissue further comprise one ormore programming instructions that, when executed, cause the processorto activate the one or more driving devices to cause the actuationcomponent to direct the pump to distribute the fluid to the targetedtissue.
 5. The system of claim 1, wherein: the pump is a syringe body;and a pressure jacket is configured to surround the syringe body andprevent the syringe body from expanding.
 6. The system of claim 6,further comprising an end plug connected to a distal portion of thesyringe body, wherein the end plug: is formed of a solid piece ofmaterial; comprises a bore therethrough for accurate distribution of thefluid; and is configured to prevent leakage of the fluid from thesyringe body.
 7. The system of claim 1, wherein the volume of fluid isabout 10 mL to about 2000 mL prior to distribution of the fluid to thetargeted tissue.
 8. The system of claim 1, wherein the fluid pressure isabout 10 psi to about 2000 psi prior to distribution of the fluid to thetargeted tissue.
 9. The system of claim 1, wherein the intracorporealsensing system comprises a sensor that is disposed at or near thetargeted tissue.
 10. The system of claim 1, wherein the one or moresensed feedback parameters comprise one or more of a tissue stretchproperty, a tissue conductivity, a tissue ultrasound property, a flowrate in the targeted tissue, a fluid cell count, a fluid particle count,and a density of a measurable tracer.
 11. The system of claim 1, furthercomprising one or more programming instructions, that, when executed,direct the processor to: monitor at least one other of the one or moreof the sensed feedback parameters while the pump distributes the fluidinto the targeted tissue at the adjusted velocity to ensure the at leastone other of the one or more of the sensed feedback parameters remainwithin the acceptable range.
 12. The system of claim 11, furthercomprising one or more programming instructions, that, when executed,direct the processor to: if the at least one other of the one or more ofthe sensed feedback parameters is not within the acceptable range duringthe directing the pump to distribute the fluid in to the targeted tissueat the adjusted velocity programming instruction, direct the system toperform at least one process selected from alert a user that the atleast one other of the one or more of the sensed feedback parameters isapproaching a limit of the acceptable range, control the adjustedvelocity so that the at least one other of the one or more of the sensedfeedback parameters remains returns to the acceptable range, alert theuser that the at least one other of the one or more of the sensedfeedback parameters is outside the acceptable range and hold theadjusted velocity, alert the user that the at least one other of the oneor more of the sensed feedback parameters is outside the acceptablerange and require an action by the user, and stop the injection.
 13. Amethod for automatically and intelligently delivering a fluid to atargeted tissue, the method comprising: directing, by a processor, apump to distribute the fluid to the targeted tissue at an initialvelocity; receiving, by the processor, one or more signals from anintracorporeal sensing system, wherein the one or more signalscorrespond to one or more sensed feedback parameters at the targetedtissue, wherein the one or more sensed feedback parameters comprise oneor more of pressure in a receiving vessel, pressure in the targetedtissue, an image property, a tissue stretch property, a tissueconductivity, a tissue ultrasound property, a flow rate in the targetedtissue, a fluid cell count, a fluid particle count, and a density of ameasurable tracer; determining, by the processor, whether the one ormore sensed feedback parameters are within an acceptable range; if theone or more sensed feedback parameters are not within the acceptablerange, determining, by the processor, an adjusted velocity; anddirecting, by the processor, the pump to distribute the fluid to thetargeted tissue at the adjusted velocity.
 14. The method of claim 13,further comprising: receiving, by the processor, one or more inputs,wherein the one or more inputs correspond to data that defines theacceptable range.
 15. The method of claim 13, further comprisingdirecting, by the processor, a display to display one or more of datacorresponding to the acceptable range in a user-readable format and theone or more sensed feedback parameters in the user-readable format. 16.The method of claim 13, wherein directing the pump to distribute thefluid to the targeted tissue further comprises causing, by theprocessor, one or more driving devices to activate, wherein activationof the one or more driving devices causes an actuation component todirect the pump to distribute the fluid to the targeted tissue.
 17. Themethod of claim 13, wherein directing the pump to distribute the fluidto the targeted tissue further comprises directing the pump todistribute about 10 mL to about 2000 mL of the fluid to the targetedtissue.
 18. The method of claim 13, wherein directing the pump todistribute the fluid to the targeted tissue further comprises directingthe pump to distribute the fluid at a pressure of about 10 psi to about2000 psi.
 19. The method of claim 13, wherein the one or more sensedfeedback parameters comprise one or more of a tissue stretch property, atissue conductivity, a tissue ultrasound property, a flow rate in thetargeted tissue, a fluid cell count, a fluid particle count, and adensity of a measurable tracer.
 20. The method of claim 13, furthercomprising monitoring at least one other of the one or more of thesensed feedback parameters while the pump distributes the fluid into thetargeted tissue at the adjusted velocity to ensure the at least oneother of the one or more of the sensed feedback parameters remain withinthe acceptable range.
 21. The method of claim 20, further comprising ifthe at least one other of the one or more of the sensed feedbackparameters is not within the acceptable range during the directing thepump to distribute the fluid into the targeted tissue at the adjustedvelocity step, directing the system to perform at least one processselected from alert a user that the at least one other of the one ormore of the sensed feedback parameters is approaching a limit of theacceptable range, controlling the adjusted velocity so that the at leastone other of the one or more of the sensed feedback parameters remainsreturns to the acceptable range, alerting the user that the at least oneother of the one or more of the sensed feedback parameters is outsidethe acceptable range and hold the adjusted velocity, alerting the userthat the at least one other of the one or more of the sensed feedbackparameters is outside the acceptable range and require an action by theuser, and stopping the injection.